Jeffrey I Cohen

National Institute of Allergy and Infectious Diseases, 베서스다, Maryland, United States

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Publications (151)1025.7 Total impact

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    ABSTRACT: Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because there have been only two genomes determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage clinical isolate strain, each from a different geographical area. In this study we report the near-complete genome sequences of 34 HSV-2 low passage and laboratory strains, of which 14 were collected in Uganda, 1 in South Africa, 11 in the USA and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low passage SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability are central to preventing and treating genital herpes. However, only two full-length HSV-2 genomes have been reported. In his study we have sequenced 34 additional HSV-2 low passage and laboratory viral genomes and have initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution.
    Journal of Virology 05/2015; DOI:10.1128/JVI.01303-15 · 4.65 Impact Factor
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    ABSTRACT: Severe chronic active Epstein-Barr virus (CAEBV) disease is defined as a severe progressive illness lasting 6 months or longer with infiltration of tissues with EBV-positive lymphocytes, markedly elevated levels of EBV DNA in the blood, and no known immunodeficiency such as HIV. These patients usually have fever, splenomegaly, lymphadenopathy, and may have markedly elevated EBV antibody titers to viral capsid antigen. Although the cause of most cases of severe CAEBV is unknown, one well-documented case was associated with compound heterozygous mutations in PRF1 (perforin 1). Here we report a patient with prolonged severe CAEBV who underwent bone marrow transplant for his disease and subsequently was found to have compound heterozygous mutations in STXBP2 (MUNC18-2) as well as a heterozygous mutation in PRF1 (perforin 1).
    Journal of Clinical Immunology 05/2015; DOI:10.1007/s10875-015-0168-y · 2.65 Impact Factor
  • Jeffrey I Cohen
    New England Journal of Medicine 04/2015; 372(22). DOI:10.1056/NEJMe1505050 · 54.42 Impact Factor
  • XueQiao Liu, Jeffrey I. Cohen
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    ABSTRACT: The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections. Published by Elsevier Inc.
    Virology 03/2015; 479-480. DOI:10.1016/j.virol.2015.02.040 · 3.28 Impact Factor
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    Jeffrey I Cohen
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    ABSTRACT: Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis (IM) and is associated with epithelial cell malignancies such as nasopharyngeal carcinoma and gastric carcinoma, as well as lymphoid malignancies including Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. EBV vaccines to prevent primary infection or disease, or therapeutic vaccines to treat EBV malignancies have not been licensed. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which is the major target of neutralizing antibody. A single phase 2 trial of an EBV gp350 vaccine has been reported; the vaccine reduced the rate of IM but not virus infection. The observation that infusion of EBV-specific T cells can reduce disease due to Hodgkin lymphoma and nasopharyngeal carcinoma provides a proof of principle that a therapeutic vaccine for these and other EBV-associated malignancies might be effective. Most therapeutic vaccines have targeted EBV LMP2 and EBV nuclear antigen-1. As EBV is associated with nearly 200 000 new malignancies each year worldwide, an EBV vaccine to prevent these diseases is needed.
    01/2015; 4(1):e32. DOI:10.1038/cti.2014.27
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    ABSTRACT: No Herpes simplex virus type-2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular injection of HSV-2 gB and gD proteins in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) and gD (gDsec), but not PsV expressing cytoplasmic or membrane-bound forms, induced circulating and intravaginal tissue resident memory CD8(+) T cells able to secrete IFN-γ and TNF-α and moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec/gDsec vaccines conferred improved survival after HSV-2 vaginal challenge compared to HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with reduced severity of genital lesions and lower viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with soluble HSV-2 gD in alum and monophosphoryl lipid A (gD2t/Alum/MPL) elicited high neutralizing antibody titers and improved survival, but did not reduce genital lesions and viral shedding. Vaccination combining HPV-gBsec/gDsec ivag and gD2t/Alum/MPL i.m. improved survival and reduced genital lesions and viral shedding. Finally, circulating HSV-2-specific CD8(+) T cells, not serum antibodies, correlated with reduced viral shedding. Together our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.
    Journal of Virology 10/2014; 89(1). DOI:10.1128/JVI.02380-14 · 4.65 Impact Factor
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    ABSTRACT: A high-throughput test to detect varicella-zoster virus (VZV) antibody in varicella vaccine recipients is not available. One of the most sensitive tests to detect VZV antibodies after vaccination is the fluorescent antibody to membrane antigen test (FAMA). Unfortunately, this test is labor intensive, somewhat subjective to read, and not commercially available. Therefore, we developed a highly quantitative and high-throughput luciferase immunoprecipitation systems (LIPS) assay to detect antibody to VZV glycoprotein E (gE). Testing of children who received the varicella vaccine showed that the gE LIPS assay had 90% sensitivity and 70% specificity, a viral capsid antigen ELISA assay had 67% and 87% specificity, and a glycoprotein ELISA (not commercially available in the US) had 94% sensitivity and 74% specificity, compared with the FAMA test. Rates of antibody detection by the gE LIPS and glycoprotein ELISA were not statistically different. Therefore, the gE LIPS assay may be useful for detecting VZV antibody in varicella vaccine recipients.
    Clinical and vaccine Immunology: CVI 07/2014; 21(9). DOI:10.1128/CVI.00250-14 · 2.37 Impact Factor
  • Clinical Infectious Diseases 07/2014; 59(1):136-7. DOI:10.1093/cid/ciu197 · 9.42 Impact Factor
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    ABSTRACT: Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 05/2014; DOI:10.1016/j.jcv.2013.07.010 · 3.47 Impact Factor
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    ABSTRACT: Herpesvirus capsid morphogenesis occurs in the nucleus, while final maturation takes place in the cytosol, requiring translocation of capsids through the nuclear envelope. The nuclear egress complex, consisting of homologs of herpes simplex virus pUL31 and pUL34, is required for efficient nuclear egress via primary envelopment and de-envelopment. Recently, we described an alternative mode of nuclear escape by fragmentation of the nuclear envelope induced by replication-competent pUL31 and pUL34 deletion mutants of the alphaherpesvirus pseudorabies virus (PrV), which had been selected by serial passaging in cell culture. Both passaged viruses carry congruent mutations in seven genes, including UL46, which encodes one of the major tegument proteins. Herpesvirus pUL46 homologs have recently been shown to activate the PI3K-Akt and ERK1/2 signaling pathways, which are involved in regulation of mitosis and apoptosis. Since in uninfected cells fragmentation of the nuclear envelope occurs during mitosis and apoptosis, we analyzed whether pUL46 of PrV is involved in signaling events impairing the integrity of the nuclear envelope. We show here that PrV pUL46 is able to induce phosphorylation of ERK1/2 and, thus, expression of ERK1/2 target genes but fails to activate the PI3K-Akt pathway. Deletion of UL46 from PrV-Delta UL34Pass and PrV-Delta UL31Pass or replacement by wild-type UL46 resulted in enhanced nuclear envelope breakdown, indicating that the mutations in pUL46 may limit the extent of NEBD. Thus, although pUL46 induces ERK1/2 phosphorylation, controlling the integrity of the nuclear envelope is independent of the ERK1/2 signaling pathway.
    Journal of Virology 03/2014; 88(11). DOI:10.1128/JVI.00501-14 · 4.65 Impact Factor
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    ABSTRACT: Mammalian cells activate DNA damage response pathways in response to virus infections. Activation of these pathways can enhance replication of many viruses, including herpesviruses. Activation of cellular ATM results in phosphorylation of H2AX and recruits proteins to sites of DNA damage. We found that varicella-zoster (VZV) infected cells had elevated levels of phosphorylated H2AX and phosphorylated ATM and that these levels increased in cells infected with VZV deleted for ORF61 or ORF63, but not deleted for ORF67. Expression of VZV ORF61, ORF62, or ORF63 alone did not result in phosphorylation of H2AX. While BGLF4, the Epstein-Barr virus homolog of VZV ORF47 protein kinase, phosphorylates H2AX and ATM, neither VZV ORF47 nor ORF66 protein kinase phosphorylated H2AX or ATM. Cells lacking ATM had no reduction in VZV replication. Thus, VZV induces phosphorylation of H2AX and ATM and this effect is associated with the presence of specific VZV genes in virus-infected cells.
    Virology 03/2014; s 452–453:52–58. DOI:10.1016/j.virol.2013.12.039 · 3.28 Impact Factor
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    Vaccine 01/2014; 32(14). DOI:10.1016/j.vaccine.2014.01.052 · 3.49 Impact Factor
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    ABSTRACT: Background Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans. Objectives We sought to determine whether primate workers, including those with injuries from animals, might be infected asymptomatically with RhCMV. Study design We developed serologic assays that distinguish RhCMV from HCMV antibodies. We tested two groups of primate workers: those with documented injuries or mucosal splashes associated with rhesus macaques, and those with no documented exposure who worked with these animals. Results None of over 200 primate workers, including 119 with injuries or mucosal splashes associated with exposures to macaques, were seropositive for RhCMV. Conclusions The frequency of asymptomatic RhCMV infection in persons who work with rhesus macaques was <0.5% (<1/200 primate workers).
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    ABSTRACT: Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons. We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren's syndrome (SjS) to determine if their antibody profiles differed from control subjects. The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005), and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls. The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.
    PLoS ONE 12/2013; 8(12):e81635. DOI:10.1371/journal.pone.0081635 · 3.53 Impact Factor
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    ABSTRACT: Rhesus cytomegalovirus (RhCMV) 68-1 is the prototypic strain of RhCMV that has been used for pathogenesis and vaccine development. We determined the complete sequence of the RhCMV 68-1 UL/b' region directly from the original urine from which RhCMV 68-1 was isolated in 1968, and compared it to other RhCMVs. The laboratory passaged RhCMV 68-1 has inversions, deletions, and stop codons in UL/b' that are absent in the original isolate and other low passage RhCMV isolates. Fourteen of the 17 open reading frames (ORFs) in 68-1 UL/b' in the original isolate share >95% amino acid identity with low passage RhCMV. The original isolate retains 6 ORFs that encode α-chemokine-like proteins, including RhUL146 and RhUL146b that share only 92% and 81% amino acid identity, respectively, with a contemporary low passage RhCMV isolate. Identification of the original RhCMV 68-1 UL/b' sequence is important for using RhCMV 68-1 in pathogenesis and vaccine studies.
    Virology 12/2013; 447(1-2):208-12. DOI:10.1016/j.virol.2013.08.026 · 3.28 Impact Factor
  • Xueqiao Liu, Jeffrey I Cohen
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    ABSTRACT: Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. VZV induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of pro-apoptotic proteins Bim and BAD, but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduce their pro-apoptotic activity, this may prevent or delay apoptosis in VZV-infected cells. Phosphorylation of Bim, but not BAD, in VZV-infected cells was dependent on activation of the MEK/ERK pathway. Cells knocked-down for Bim showed delayed VZV plaque formation resulting in longer survival of VZV-infected cells and increased replication of virus, compared with wild-type cells infected with virus. Conversely, overexpression of Bim resulted in earlier plaque formation, smaller sized plaques, reduced virus replication, and increased caspase 3 activity. Inhibition of caspase activity in VZV-infected cells overexpressing Bim restored levels of virus production similar to those seen with virus-infected wild-type cells. Previously we showed that VZV ORF12 activates ERK and inhibits apoptosis in virus-infected cells. Here we found that VZV ORF12 contributes to Bim and BAD phosphorylation. In summary, VZV triggers Bim phosphorylation; reduction of Bim levels results in longer survival of VZV-infected cells and increased VZV replication.
    Journal of Virology 11/2013; 88(2). DOI:10.1128/JVI.01695-13 · 4.65 Impact Factor
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    ABSTRACT: The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.
    Nature Immunology 10/2013; DOI:10.1038/ni.2771 · 24.97 Impact Factor
  • Caren G. Solomon, Jeffrey I. Cohen
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    ABSTRACT: A 65-year-old man presents with a rash of 2 days' duration over the right forehead with vesicles and pustules, a few lesions on the right side and tip of the nose, and slight blurring of vision in the right eye. The rash was preceded by tingling in the area and is now associated with aching pain. How should this patient be evaluated and treated?
    New England Journal of Medicine 07/2013; 369(3):255-263. DOI:10.1056/NEJMcp1302674 · 54.42 Impact Factor
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    ABSTRACT: The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.
    Science 07/2013; 341(6142):186-191. DOI:10.1126/science.1240094 · 31.48 Impact Factor
  • Journal of the American Academy of Dermatology 06/2013; 68(6):1046-7. DOI:10.1016/j.jaad.2012.12.972 · 5.00 Impact Factor

Publication Stats

5k Citations
1,025.70 Total Impact Points

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Institutions

  • 1994–2015
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      베서스다, Maryland, United States
  • 2008–2014
    • National Institute of Allergy and Infectious Disease
      베서스다, Maryland, United States
    • Fox Chase Cancer Center
      Philadelphia, Pennsylvania, United States
  • 2013
    • Leidos Biomedical Research
      Фредерик, Maryland, United States
  • 1988–2013
    • National Institutes of Health
      • • Laboratory of Infectious Diseases
      • • Branch of Science of Research and Technology
      • • Laboratory of Clinical Infectious Diseases
      • • National Institute of Allergy and Infectious Diseases (NIAID)
      • • Laboratory of Clinical Investigation (LCI)
      베서스다, Maryland, United States
  • 2009
    • U.S. Food and Drug Administration
      • Center for Biologics Evaluation and Research
      Washington, Washington, D.C., United States
  • 2005
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2002
    • Texas A&M University - Galveston
      Galveston, Texas, United States
    • Georgia State University
      Atlanta, Georgia, United States
  • 1995
    • University of Liège
      • Laboratory of Fundamental Virology
      Luik, Walloon, Belgium